TAK1 inhibition ameliorates survival from graft-versus-host disease in an allogeneic murine marrow transplantation model

Ayako Kobayashi, Shinichi Kobayashi, Kosuke Miyai, Yukiko Osawa, Toshikatsu Horiuchi, Shoichiro Kato, Takaaki Maekawa, Takeshi Yamamura, Junichi Watanabe, Ken Sato, Hitoshi Tsuda, Fumihiko Kimura

Acute graft-versus-host disease (GVHD) is a major cause of morbidity and mortality in allogeneic hematopoietic cell transplantation (allo-HCT). Majority of the current immunosuppressive strategies targeting donor T cells to prevent or treat acute GVHD are only partially effective, and often require escalated immunosuppressive therapy. Recent studies have revealed that activation of antigen-presenting cells in the proinflammatory milieu is important for the priming and promotion of GVHD. This activation is mediated by innate immune signaling pathways, which therefore potentially represent new targets in addressing GVHD. Using gene expression analysis of peripheral monocytes from patients' post-allo-HCT, we detected an upregulation of TGF-β-activated kinase 1 (TAK1), a key regulator of the toll-like receptor signaling pathway. 5Z-7-oxozeaenol, a selective inhibitor of TAK1, reduced proinflammatory cytokine production by activated monocytes under lipopolysaccharide stimulation and T cell proliferation in allogeneic-mixed leukocyte reactions with monocyte-derived dendritic cells. In an experimental mouse model of GVHD, 5Z-7-oxozeaenol administration after allo-HCT ameliorated GVHD severity and mortality, with significant reduction in serum TNFα, IL-1β, and IL-12 levels. Our findings suggest that altering the activation status of innate immune cells by TAK1 inhibition may be a novel therapeutic approach for acute GVHD.